This application, in response to PAR-07-159 (National Cooperative Drug Discovery Groups for the Treatment of Mental Disorders, Drug or Alcohol Addiction), represents the resubmission of the competitive renewal application of "The Emory-MSSM-GSK-NIMH Collaborative Mood and Anxiety Disorders Initiative", MH-069056. This unique opportunity to accelerate antidepressant and anxiolytic drug development brings together expertise of four complementary research groups: the Emory University School of Medicine Department of Psychiatry and Behavioral Sciences, the NIMH Intramural Mood and Anxiety Disorders Program, the Mt. Sinai School of Medicine Department of Psychiatry (MSSM) and the Center for Excellence in Drug Discovery (CEDD) in Psychiatry of GlaxoSmithKline (GSK), one of the largest multinational pharmaceutical companies. The two major goals of the current application are the development of innovative new models for basic and clinical research in mood and anxiety disorders and the intensive scrutiny of 3 novel GSK antidepressant/anxiolytic candidates [two structurally distinct CRP! receptor antagonists (GSK008 and CRF-002), and a 5-HTiA/IB/ID receptor antagonist (GSK-1), in preclinical and clinical paradigms. In addition to an Administrative and Genomics/Endocrine/Statistics Core, 5 research projects are proposed. The preclinical projects are based at Emory University and are led by established investigators including, Michael Davis, PhD (Rat Models of Anxiety), Donald Rainnie, PhD (Physiologic Actions of Novel Antidepressants/Anxiolytics in the Basolateral Amygdala), and Clinton D. Kilts, PhD and Mark Goodman, PhD, (CRFi receptor PET Ligand Development). One clinical project is based in the intramural NIMH program: Effects of novel antidepressants/anxiolytics on human startle in normal volunteers (Christian Grillon, PhD, PI). A placebo-controlled, double-blind trial (based at Emory: Barbara Rothbaum, PhD, PI and MSSM: Dennis Charney, MD, PI) will assess the efficacy of the CRFi receptor antagonist GSK008 in patients with post-traumatic stress disorder (PTSD). This proposal encompasses virtually all of the major goals outlined in the PAR, namely, development of new neurochemical tools including PET ligands, exploration of new models for drug development and facilitation of a partnership between academia, NIMH and industry.